Trophoblast cell-surface antigen (Trop-2), also referred to as M1S1, GA733-1 (gastric antigen 733-1), EGP-1 (epithelial glycoprotein-1), or TACSTD2 (tumor-associated calcium signal transducer), is a cell surface glycoprotein originally identified in human placental trophoblast and subsequently found to be highly expressed in most human carcinomas, but showed only restricted or limited expression in normal adult tissues. See, e.g., Varughese et al., Gynecologic Oncology, 122:171-177, 2011. Trop-2 is highly conserved among species. For example, human Trop-2 protein shares 79% identity with murine Trop-2 protein. See Cubas et al., Molecular Cancer, 9:253, 2010. Although the biological role of Trop-2 is still unclear, various studies have shown that overexpression of Trop-2 correlates with increased tumor aggressiveness, metastasis, and poor prognosis in various human carcinomas, such as colon cancer, ovarian cancer, and pancreatic cancer. See, e.g., Fang et al., Int. J. Colorectal Dis, 24:875-884, 2009; Bignotti et al., Eur. J. Cancer, 46:944-953, 2010; and Fong et al., Br J Cancer, 99:1290-1295, 2008. Studies have also shown that Trop-2 contributes to tumor pathogenesis at least in part by activating the ERK1/2 MAPK pathway which has important implications in cancer cell proliferation, migration, invasion, and survival. See Cubas et al., 2010, supra.
Overexpression of Trop-2 by epithelial tumor cells and its transmembrane location render Trop-2 an attractive target for cancer immunotherapy. Accordingly, a high affinity antibody to Trop-2, particularly to human Trop-2, would make a superior therapeutic agent for cancer treatment in human patients. Although various Trop-2 antibodies have been disclosed (see, e.g., U.S. Pat. No. 7,420,041 (antibody AR47A6.4.2), U.S. Pat. No. 5,850,854 (antibody BR110), U.S. Pat. No. 6,653,104 (antibody RS7), U.S. Pat. No. 7,517,964 (antibody RS7), US2012/0237518), it has been exceedingly difficult to identify monoclonal antibodies having high affinity, high specificity, and potent cytotoxic or tumor killing/inhibition/regression activity. There remains a need for antibodies and other immunotherapeutic agents (such as antibody-drug conjugates) directed against Trop-2 having improved efficacy and safety profile, and which are suitable for use with human patients.